State-dependent Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels by a Novel Peptide Toxin
| Autor: | Robert J. French, Denis McMaster, Christopher H. Thompson, Nael A. McCarty, Matthew D. Fuller, Éva Bakos, Zhi Ren Zhang, Gergely Szakács, Balázs Sarkadi, Julia Kubanek, Eszter Schay, Jan Pohl, Cody S. Freeman |
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| Rok vydání: | 2007 |
| Předmět: |
Molecular Sequence Data
Molecular Conformation Cystic Fibrosis Transmembrane Conductance Regulator Scorpion Venoms Peptide ATP-binding cassette transporter Biochemistry Xenopus laevis Chloride Channels Animals Humans Amino Acid Sequence Molecular Biology Peptide sequence Ion channel chemistry.chemical_classification Transmembrane channels Sequence Homology Amino Acid biology Chemistry Biological Transport Cell Biology Cystic fibrosis transmembrane conductance regulator Protein Structure Tertiary Cell biology Transport protein Electrophysiology Oocytes Chloride channel biology.protein Rabbits |
| Zdroj: | Journal of Biological Chemistry. 282:37545-37555 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m708079200 |
| Popis: | Peptide toxins from animal venom have been used for many years for the identification and study of cation-permeable ion channels. However, no peptide toxins have been identified that interact with known anion-selective channels, including cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis and a member of the ABC transporter superfamily. Here, we describe the identification and initial characterization of a novel 3.7-kDa peptide toxin, GaTx1, which is a potent and reversible inhibitor of CFTR, acting from the cytoplasmic side of the membrane. Thus, GaTx1 is the first peptide toxin identified that inhibits a chloride channel of known molecular identity. GaTx1 exhibited high specificity, showing no effect on a panel of nine transport proteins, including Cl(-) and K(+) channels, and ABC transporters. GaTx1-mediated inhibition of CFTR channel activity is strongly state-dependent; both potency and efficacy are reduced under conditions of elevated [ATP], suggesting that GaTx1 may function as a non-competitive inhibitor of ATP-dependent channel gating. This tool will allow the application of new quantitative approaches to study CFTR structure and function, particularly with respect to the conformational changes that underlie transitions between open and closed states. |
| Databáze: | OpenAIRE |
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